7-15-keefe.fm

Effects of Olanzapine, Quetiapine, and Risperidone on Neurocognitive Function in Early Psychosis: A Randomized, Double-Blind 52-Week ComparisonRichard S.E. Keefe, Ph.D.Objective: The authors sought to com-Results: At week 12, there was significantJohn A. Sweeney, Ph.D.
treatment (p<0.01), but no significant
function in patients with early psychosis.
overall difference between treatments.Composite z score improvements on the
Hongbin Gu, Ph.D.Method: In a 52-week double-blind,Robert M. Hamer, Ph.D.
the course of psychotic illness (<5 years)
Diana O. Perkins, M.D.
tiapine (100–800 mg/day), or risperidone
olanzapine, 0.34 for quetiapine, and 0.22
Joseph P. McEvoy, M.D.
for risperidone. Statistically significant re-
Jeffrey A. Lieberman, M.D.
and 2.4 mg (SD=1.0) for risperidone. A to-
tal of 224 patients completed neurocogni-tive assessments at baseline and at 12
Conclusions: Olanzapine, quetiapine,
psychosis patients. Although cognitive im-
neurocognitive battery used in the Clini-
cal Antipsychotic Trials of Intervention Ef-
fectiveness (CATIE) and from the Brief As-
sessment of Cognition in Schizophrenia.(Am J Psychiatry 2007; 164:1061–1071)
In patients with schizophrenia, neurocognitive defi- with treatment and functional improvement in patients
cits have been established as an important symptom do-
main associated with long-term outcome. On average,
Treatment with atypical antipsychotics has been found,
these patients perform one to two standard deviations
in various studies, to produce improvements in neurocog-
below healthy individuals on neurocognitive measures,
nitive performance in schizophrenia (3, 13–23; see also the
such as those assessing attention, executive function,
meta-analyses in references 20, 24, 25 and early psychosis
memory, and processing speed (1, 2). These deficits are
in references 8–10). However, the comparator medication
clearly present at the first episode of illness (3–5), even in
in many of these studies was a conventional antipsychotic
antipsychotic-naive patients (6, 7), and thus are not a
administered at doses large enough to produce substan-
deleterious effect of treatment. These deficits appear to
tial extrapyramidal symptoms requiring treatment with
be only marginally corrected with conventional antipsy-
anticholinergics, and both of these classes of medication
chotic agents in patients early in the course of psychotic
are associated with impaired cognition (20). In previous
illness, even when medication is administered at lower
studies, antipsychotic-naive patients with early psychosis
receiving olanzapine (8, 9) or risperidone (10) demon-
Because neurocognitive deficits are among the stron-
strated greater neurocognitive improvement than those
gest predictors of functional outcome in patients with
receiving haloperidol, even when haloperidol was given in
schizophrenia (5, 11, 12), interventions that reduce these
low doses. In this study, we compared the neurocognitive
deficits may be particularly useful; neurocognitive im-
effects of olanzapine and risperidone and a third atypical
provement may enhance patients’ recovery and func-
antipsychotic, quetiapine. Our primary hypothesis was
tional life outcomes. However, little research has exam-
that the three agents would be equivalent in their effects
ined the relationship between cognitive improvement
This article is featured in this month’s AJPAudio and is discussed in an editorial by Dr. Green on p. 992.COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICSTABLE 1. Neurocognitive Domains Assessed by Tests in the CATIE Neurocognitive Battery and the BACSa
Controlled Oral Word Association Test: F, A, and S words
Verbal fluency: letter fluency (F and S words or P
Category instances: animals, fruits, and vegetables
Wechsler Adult Intelligence Scale—Revised, digit symbol
Wisconsin Card Sorting Test, 64-card version
Wechsler Intelligence Scale for Children, 3rd ed., mazes
Computerized Test of Visuospatial Working Memory
Continuous Performance Test—Identical pairs: 2,3, and 4
a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; BACS=Brief Assessment of Cognition in Schizophrenia.b MATRICS=Measurement and Treatment Research to Improve Cognition in Schizophrenia.
This study is the first head-to-head comparison of the
We excluded patients who did not speak English; had a history
cognitive effects of atypical antipsychotics in early psy-
of mental retardation; were pregnant or nursing; had a serious,unstable medical illness; had a known allergy to one of the study
chosis. In this article, we examine the effects of olanza-
medications; were at serious risk of suicide; or had participated in
pine, quetiapine, and risperidone on neurocognitive func-
an investigational drug trial within 30 days before the first treat-
tion in patients early in the course of psychotic illness and
the relationship of cognitive changes to changes in func-
Study Treatments
tioning and quality of life. In a companion article in thisissue (26), we report results for the primary outcome
Patients were randomly assigned to treatment with olanzapine
(2.5–20 mg/day), quetiapine (100–800 mg/day), or risperidone
measure of all-cause treatment discontinuation and sec-
(0.5–4 mg/day). On days 1 and 2, each patient received one cap-
ondary measures of psychopathology, quality of life, and
sule of olanzapine (2.5 mg), quetiapine (100 mg), or risperidone
(0.5 mg) in the evening. At the treating physician’s discretion, thedose could be increased by one capsule every other day—i.e., ondays 3 and 4, one capsule in the morning and one in the evening;
on days 5 and 6, one capsule in the morning and two in theevening; and so on, up to a maximum of four capsules twice daily.
This was a 52-week randomized, double-blind, flexible-dose,
Any previous antipsychotic therapy was tapered and discontin-
multicenter study of patients early in the course of schizophrenia,
ued during the first 2 weeks of double-blind treatment, and no
schizoaffective disorder, or schizophreniform disorder assigned
subsequent use of an additional antipsychotic was permitted.
to treatment with olanzapine, quetiapine, or risperidone.
Treatment with an adjunctive antidepressant or mood stabilizerduring the first 8 weeks of treatment was not allowed unless ap-
Study Population
proved by the project medical officer. Anticholinergic medica-
Participants were recruited from inpatient, outpatient, and
tions for acute extrapyramidal side effects were permitted for up
emergency department services for the evaluation and treatment
to a total of 2 weeks over the course of the trial. Clinicians were
of psychosis. The study was approved by the institutional review
encouraged to lower the dose of antipsychotic to relieve extrapy-
board at each site, and written informed consent was obtained
ramidal side effects. Otherwise, adjunctive and concomitant
from the patients or their legally authorized representatives. Con-
medications could be used without restriction. This strategy kept
senting patients 16–40 years of age were eligible for the study if
the frequency of use for benzodiazepines, antidepressants, mood
they met DSM-IV criteria for schizophrenia, schizophreniform
stabilizers, and anticholinergics below 5% during the study.
disorder, or schizoaffective disorder. Patients had to be in the first
Assessments
episode of their psychotic illness and had to have been continu-ously ill for at least 1 month and no more than 60 months. Pa-
The screening evaluation included a diagnostic interview (the
tients were excluded if a prior psychotic episode had remitted for
Structured Clinical Interview for DSM-IV), medical history, physi-
3 months or more or if they had prior antipsychotic drug treat-
cal examination, measurement of vital signs, and laboratory tests.
ment for more than 16 cumulative weeks. Several exceptions to
Training covering the study protocol and administration of all
these criteria were allowed on a case-by-case basis: the study in-
study evaluations was provided at an investigator meeting. Cog-
cluded nine patients who had been ill for more than 60 months,
nitive testers who could not attend the meeting and raters who
seven who were over 40 years of age, and 16 who had taken anti-
joined the study after the investigator meeting participated in the
psychotics for more than 16 weeks. All patients had a score ≥4 on
same training using web-based materials, teleconferencing, and
at least one psychosis item in the Positive and Negative Syndrome
Scale (PANSS; 27) and a score ≥4 (moderately ill) on the severity of
Study visits occurred at baseline, at weekly intervals for the first
illness item of the Clinical Global Impression scale (CGI) at the
6 weeks, every other week for the next 6 weeks, and monthly
point of maximum severity of illness to date. Female participants
thereafter. Neurocognitive assessments were conducted at base-
of childbearing potential had to be using a medically acceptable
line (up to 2 weeks after the start of treatment) and at weeks 12
and 52 (up to 2 weeks before or after the target date) or when the
KEEFE, SWEENEY, GU, ET AL.TABLE 2. Baseline Characteristics of 400 Early-Psychosis Patients Randomly Assigned to Treatment With Olanzapine,Quetiapine, or Risperidonea
Parents’ highest education level less than
Clinical Global Impression scale, severity
Calgary Depression Scale for Schizophrenia,
Heinrichs-Carpenter Quality of Life Scale
a Treatment groups did not differ significantly on any characteristic.
patient terminated the study if it was before week 52. A total of
based composite score was defined as the average of the five do-
224 patients completed neurocognitive assessments at baseline
main summary scores for the CATIE neurocognitive battery.
and 12 weeks, and 81 patients also completed them at 52 weeks.
An additional neurocognitive outcome measure was the com-
Cognitive testers were not blind to adverse event status and use of
posite score on the Brief Assessment of Cognition in Schizophre-
nia (BACS; 30, 31), a briefer set of tests designed to derive a com-
The primary neurocognitive outcome measure for this study
posite score. With the BACS, we sought to determine its relative
was a composite score derived from the neurocognitive battery
sensitivity to treatment-related cognitive changes compared with
used in the Clinical Antipsychotic Trials of Intervention Effective-
the larger CATIE battery; we also wanted to enable comparisons
ness (CATIE). The performance of the 1,331 patients assessed at
between this study and other trials using the BACS. The BACS,
baseline is described in detail elsewhere (28). For the calculation
which takes approximately 35 minutes to administer, includes
of the CATIE battery composite score, all test measures were first
brief assessments of reasoning and problem solving, verbal flu-
converted to standardized z scores by setting the sample mean of
ency, processing speed, verbal memory, working memory, and
each measure at baseline to zero and the standard deviation to 1.
motor functions. The BACS composite score was calculated by
Summary scores for some tests were calculated by averaging z
summing the z scores for each of the six measures, obtained by
scores from individual measures: a Wisconsin Card Sorting Test
comparing each measure with a healthy comparison sample and
score was calculated by averaging z scores for preservative errors
dividing by the standard deviation of the healthy comparison
and categories achieved; a Continuous Performance Test score
sample (30). This composite score has high test-retest reliability
was calculated by averaging the z score of d-prime for the three
in patients with schizophrenia and healthy comparison subjects
different Continuous Performance Test conditions; and the Con-
(intraclass correlation coefficients >0.80) (30). Pearson correla-
trolled Oral Word Association Test and category instances sum-
tions between the BACS composite score and CATIE neurocogni-
mary measures were averaged together to form one summary test
tive composite score in this study were r=0.84 at baseline, r=0.86
score referred to as verbal fluency. For domains with more than
at 12 weeks, and r=0.90 at 53 weeks (all p values <0.001). Table 1
one test, summary scores were determined by calculating the
summarizes the neurocognitive domains assessed by the CATIE
mean of the z scores for the measures that comprised the domain,
then converting the mean to a z score with a mean of zero and a
Severity of psychopathology was measured with the PANSS
standard deviation of 1. This resulted in nine test summary scores
and the CGI severity item. Functional outcome was measured
and five domain scores corresponding to five of the seven do-
with the standard patient interview from the Heinrichs-Carpen-
mains in the Measurement and Treatment Research to Improve
ter Quality of Life Scale (32), emphasizing the vocational and so-
Cognition in Schizophrenia consensus battery (29). A domain-
COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICSTABLE 3. Use of Adjunctive Medicationsa by Early-Psychosis Patients During Treatment With Olanzapine, Quetiapine, orRisperidone
a Adjuctive medications include those prescribed to address an aspect of psychopathology inadequately controlled by the assigned antipsy-
FIGURE 1. Changes in CATIE Neurocognitive Battery Com-
week 12 at the 0.05 significance level. All subsequent analyses on
posite Score From Baseline to Weeks 12 and 52 in Patients
individual cognitive tests and between treatment groups were in-
Treated With Olanzapine, Quetiapine, or Risperidonea
tended to expand our major finding and should be considered ex-ploratory. Therefore, no p value adjustments were made for mul-tiple comparisons.Baseline Characteristics
Table 2 presents demographic and clinical characteris-
tics for the three treatment groups and the whole cohort.
There were no significant differences between treatment
groups. Patients demonstrated moderate levels of psycho-
pathology at baseline, as reflected in scores on the PANSS,the CGI severity item, and the Calgary Depression Scale
e in Composite Scorocognitiv 0.1Pharmacological TreatmentsChang Neur
The mean modal prescribed daily doses of study drugs
were 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215)
for quetiapine, and 2.4 mg (SD=1.0) for risperidone; the
a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness.
mean modal numbers of prescribed capsules per day were
4.7 (SD=2.1) for olanzapine, 5.1 (SD=2.2) quetiapine, and
4.7 (SD=2.0) for risperidone. Since adjunctive treatmentswere discouraged, their use was rare after baseline. The
Statistical Analysis
use of mood stabilizers, antidepressants, benzodiaz-
Analyses of the neurocognitive variables were specified in a
epines, and anticholinergics during the study is summa-
statistical analysis plan that was finalized before the blind was
rized in Table 3. There were no significant differences be-
broken. Baseline measures of demographic and clinical charac-teristics were compared using two-sided Kruskal-Wallis tests for
tween treatment groups in use of adjunctive medication.
continuous variables and Fisher’s exact test for categorical vari-ables. Separate general linear models provided least square
Effects on Neurocognition
means estimates for changes in cognitive scores from baseline to
At week 12, each of the treatments significantly im-
weeks 12 and 52 for each treatment group, adjusting for baseline
proved the composite score on the CATIE neurocognitive
and weeks of treatment in cases where neurocognitive testing wascompleted 1 to 2 weeks before or after the scheduled visit. The ef-
battery compared with baseline (p<0.01 for olanzapine,
fect of group membership on neurocognitive change scores was
p<0.001 for quetiapine and risperidone) (Table 4). There
tested using the F statistic from the model, followed by pairwise
was no significant difference between treatments in the
comparisons between treatment groups if overall treatment effect
magnitude of cognitive improvement. Mean z score im-
was significant. Pearson partial correlation coefficients were used
provements in the CATIE composite score were 0.17 for
to examine the potential linear relationships between treatment-related changes in the neurocognitive composite scores and
olanzapine, 0.33 for quetiapine, and 0.32 for risperidone
treatment-related changes in the clinical outcome measures and
the social and vocational subscale scores on the Heinrichs-Car-
There was considerable attrition at week 52, with only
penter Quality of Life Scale from baseline to weeks 12 and 52 in
81 patients providing enough neurocognitive data for the
each treatment group and in the cohort as a whole. These correla-
calculation of the CATIE composite score. The baseline
tions were adjusted for baseline cognitive and clinical measures.
The primary analysis tested the overall treatment effect on
and week 12 cognitive measures of patients who remained
CATIE neurocognitive battery composite scores from baseline to
in the study until week 52 were not significantly different
KEEFE, SWEENEY, GU, ET AL.
from those of patients who dropped out of the study. The
with a median correlation of –0.25. The correlations be-
magnitude of cognitive improvement from baseline to
tween cognitive change and change in clinical symptoms
endpoint was similar for patients who stayed through to
for the study population at week 52 had a range of –0.26 to
week 52 (0.09 for olanzapine, 0.24 for quetiapine, and 0.27
–0.44. Correlations between cognitive change and global
for risperidone) (Figure 1), but the within-group treatment
clinical change within each treatment group were mainly
effects on CATIE battery composite scores at week 12 were
in the range of medium to large (r=–0.5), with a median
correlation of –0.33 (Table 5). The correlations between
Exploratory analyses of individual neurocognitive mea-
cognitive change and symptom change tended to be larger
sures at week 12 suggested differences between treat-
ments on the following tests from the CATIE battery: ver-bal fluency, letter-number sequencing, WAIS-R digit
Relationship Between Cognitive Change and
symbol subtest, and Continuous Performance Test d-
Change in Functional Outcome
prime (Table 4). Subsequent pairwise comparisons of
As reported in the companion article (26), changes in the
treatment groups showed that at 12 weeks, the improve-
vocational and social subscales of the Heinrichs-Carpenter
ment in cognition was greater in the quetiapine group
Quality of Life Scale were small at 12 weeks (less than 0.2
than in the olanzapine group (p<0.05) on measures of ver-
standard deviations) and in the range of medium effects
bal fluency, the WAIS-R digit symbol subtest, and the Con-
(about 0.5 standard deviations) for each treatment group at
tinuous Performance Test d-prime. Compared with the
52 weeks. In analyses of the total study population pooled
risperidone group at 12 weeks, the improvement in cogni-
across treatment groups at week 12 (N=219), partial corre-
tion was greater in the quetiapine group (p<0.05) on mea-
lations between change in the CATIE neurocognitive bat-
sures of verbal fluency and the WAIS-R digit symbol sub-
tery composite score and change in Heinrichs-Carpenter
test. The improvement in cognition was greater in the
Quality of Life Scale subscores, controlling for baseline
risperidone group than in the olanzapine group (p<0.05)
CATIE composite score and PANSS total score, were 0.14
on letter-number sequencing at 12 weeks. No other pair-
(p=0.04) for vocational outcomes and 0.18 (p=0.009) for oc-
wise comparisons were significant, and there were no sig-
cupational outcomes. These partial correlations were
nificant differences between treatments for individual
slightly larger at week 52 (N=77; r=0.22 [p=0.056] to 0.36 [p=
0.001]). Within-treatment correlations between cognitive
Relationship Between Cognitive Change and
change and functional change are presented in Figure 2.Symptom Change
Regression analyses conducted to further examine the re-lationship between cognitive, symptom, and functional
As reported in the companion article in this issue (26),
symptom reduction as rated on the PANSS and the CGI se-
change suggested that the variance in social and voca-
verity item was substantial in each treatment group, rang-
tional functioning predicted by the CATIE composite score
ing from 11.6 to 14.3 points on PANSS total score and 0.8 to
was not statistically significant when additionally con-
0.9 points on the CGI severity item score at 12 weeks, and
trolled for change in PANSS score during treatment.
15.6 to 18.5 points on PANSS total score and 1.2 to 1.3
Relationship Between Cognitive Change and
points on the CGI severity score at 52 weeks. Correlations
Changes in Side Effects
between the CATIE neurocognitive battery compositescore and symptom changes at week 12 for the entire
Correlations between cognitive change and changes in
study population were small, ranging from –0.18 to –0.26.
side effects, as measured by scores at 12 and 52 weeks on
Within treatment groups, the majority of the 15 correla-
the Abnormal Involuntary Movement Scale (33), the
tions between change in CATIE composite score and
Barnes Rating Scale for Drug-Induced Akathisia (34), and
change in PANSS or CGI severity score at week 12 were in
the Simpson-Angus Rating Scale (35), were not statistically
the effect size range of small (r=–0.1) to medium (r=–0.3),
significant. Use of anticholinergic treatment or presence
COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICSTABLE 4. Least Square Mean (LSM) Change From Baseline on Neurocognitive Tests in Early-Psychosis Patients at Weeks 12and 52 of Treatment With Olanzapine, Quetiapine, or Risperidonea
telligence Scale—Revised, digit symbol subtest
ing Test, 64-card version, mean z score of persever-ative errors and categories completed
gence Scale for Children, 3rd ed., mazes subtest
ing Memory Test, mean error, 5 and 15 sec minus no delay (cm)
mance Test, iden-tical pairs, mean z score of d-prime for 3 trials
score (compared with published healthy comparison data)
a Analyzed using a general linear model. Least square mean data are raw scores, adjusting for baseline and weeks of treatment.b Week 12: A=overall effect between antipsychotic treatment groups, p<0.05; B=improvement from baseline with quetiapine, p<0.05; C=im-
provement from baseline with risperidone, p<0.05; D=improvement from baseline with olanzapine, p<0.05; E=quetiapine versus risperi-done, p<0.05; F=quetiapine versus olanzapine, p<0.05; G=olanzapine versus risperidone, p<0.05. Week 52: H=overall effect between anti-psychotic treatment groups, p<0.05; I=improvement from baseline with quetiapine, p<0.05; J=improvement from baseline withrisperidone, p<0.05; K=improvement from baseline with olanzapine, p<0.05; L=quetiapine versus risperidone, p<0.05; M=quetiapine ver-sus olanzapine, p<0.05; N=olanzapine versus risperidone, p<0.05.
c CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; BACS=Brief Assessment of Cognition in Schizophrenia.KEEFE, SWEENEY, GU, ET AL.COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICSFIGURE 2. Partial Pearson Correlations Between Change in
rocognitive test performance. There were no significant
CATIE Neurocognitive Battery Composite Score and Change
differences between treatments in overall cognitive com-
in Functional Outcome Measures From Baseline to Weeks
posite scores, which suggests that quetiapine may provide
12 and 52, Controlling for Baseline CATIE Composite Scoreand PANSS Total Scorea
modest cognitive benefit to patients with early psychosisthat is in line with that provided by olanzapine and risperi-done. Improvement in the cognitive composite scores was
significantly associated with improved social and occupa-
tional functioning as measured by the Heinrichs-Carpen-
earson r) 0.6
ter Quality of Life Scale. This result is the first direct evi-
dence that antipsychotic treatment-related cognitive
ith Chang
changes in patients with early psychosis may be clinically
relevant for occupational and social functioning. How-
ever, interpretation of this relationship is tempered byanalyses indicating that symptom change and baseline
ocognitiv
cognitive scores also predicted the variance in functional
Composite Scor
outcomes. Thus, cognitive improvement may be a part of
a general treatment response that is associated with im-
The magnitude of neurocognitive improvement for
olanzapine and risperidone in this study is slightly less
Heinrichs-Carpenter Quality of Life Scale
than that previously reported in comparisons with conven-
a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness;
tional antipsychotics in early-psychosis patients (8–10). In
PANSS=Positive and Negative Syndrome Scale
earlier studies that used doses similar to those we used in
this study (8, 9), the magnitude of the effect of olanzapineon neurocognitive composite scores was 0.36 at 12 weeks
of sleepiness or akinesia was not significantly related to
and 0.56 at 52 weeks; in this study, olanzapine’s effect was
cognitive performance at 12 or 52 weeks.
weaker, with effect sizes of 0.17 and 0.09 at 12 and 52weeks, respectively. The magnitude of the effect of risperi-
Relationship Between CATIE Neurocognitive
done on neurocognition in an earlier study (10) was 0.4 at
Battery and BACS
12 weeks, whereas in this study, effect sizes for risperidone
Treatment effects on the BACS composite score were
were 0.32 and 0.27 at 12 and 52 weeks, respectively.
similar to those on the CATIE battery composite score. The
The reason for the lesser effect of olanzapine and ris-
BACS data are described in more detailed tables and fig-
peridone on neurocognition in this study compared with
ures in a data supplement that accompanies the online
previous studies is not entirely clear. These differences in
version of this article. A total of 214 patients completed
magnitude are small and could be due to random factors
both the CATIE and BACS batteries at baseline and 12
or to methodological advances in the current study that
weeks, and 76 completed both batteries at baseline and 52
may have served to refine the estimate of the magnitude of
weeks. For the entire cohort, change in the CATIE compos-
cognitive treatment effects, such as the inclusion of alter-
ite score was highly correlated with change in the BACS
nate verbal memory tests, which is likely to yield lower es-
composite score at 12 weeks (r=0.57, df=212, p<0.001) and
timates of improvement because of repeated test exposure
at 52 weeks (r=0.70, df=74, p<0.001). The BACS composite
(8–10). Another possible factor is prior exposure to anti-
score changes were 0.19 for olanzapine (p<0.01), 0.34 for
psychotics. Patients who are antipsychotic-naive when
quetiapine (p<0.001), and 0.22 for risperidone (p<0.01),
beginning treatment have been shown to obtain particu-
similar to those of the CATIE battery. Between-groups
larly large benefits from treatment with atypical antipsy-
comparisons of individual BACS measures and correla-
chotics (9). While about three-quarters of the patients in
tions with symptom and side effect change paralleled the
this study and in the earlier olanzapine study had briefly
CATIE battery findings, with slightly more (4 of 12) signifi-
received treatment with antipsychotics prior to random-
cant relationships with functional outcomes.
ization, in this more recent study the medications receivedpreviously were more likely to have been atypical antipsy-
Discussion
chotics, particularly olanzapine or risperidone. Patientswho were randomly assigned to the same medication that
This is the first randomized, double-blind study com-
they were receiving at or before baseline may have had a
paring the neurocognitive effects of atypical antipsychotic
reduced neurocognitive response to further treatment
agents in the treatment of patients early in the course of
(36). Moreover, patients were given a 2-week window after
psychotic illness. Olanzapine, quetiapine, and risperidone
treatment initiation to complete baseline neurocognitive
produced modest but significant improvements in neu-
testing. Thus, very early cognitive effects of antipsychotic
KEEFE, SWEENEY, GU, ET AL.TABLE 5. Pearson Correlations Between Change in CATIE Neurocognitive Battery Composite Score and Change in ClinicalOutcome Measures From Baseline to Weeks 12 and 52 in Early-Psychosis Patients During Treatment With Olanzapine,Quetiapine, or Risperidonea
Clinical Global Impression, severity item
a Negative correlations imply that as cognition improved, symptoms diminished.*p<0.05. **p<0.01. ***p<0.001.
treatment might have occurred in some of these patients,
The course of cognitive improvement with atypical an-
which may have minimized measurements of cognitive
tipsychotics is controversial. While some long-term stud-
ies have reported increasing cognitive improvement over
The significant benefit of quetiapine treatment on neu-
time (9, 41), others have not (42). Furthermore, the addi-
rocognitive measures in patients with early psychosis is a
tional cognitive benefit over time may depend on signifi-
new observation. Previous work has suggested that olan-
cant patient attrition (9). Grouped data from all studies of
zapine (8, 9) and risperidone (10) provide greater cognitive
atypical antipsychotics suggest little additional cognitive
benefit than low doses of haloperidol in patients with early
benefit beyond the initial gains in the early phases (6–10
psychosis. Our findings in this study suggest that the effect
weeks) of treatment (unpublished 2004 analysis of R.
of quetiapine on cognition may be as beneficial as that of
Keefe and J. Cone). Our findings in this study support this
olanzapine or risperidone, and thus this agent may be an-
view, as the magnitude of cognitive improvements across
other evidence-based alternative for clinicians who focus
all domains was similar at 12 and 52 weeks, suggesting
on cognitive outcomes. However, results from a recent
that most of the cognitive benefit of atypical antipsychot-
study of 240 schizophrenia patients with stable symptoms
ics occurs in the first few months of treatment. This find-
treated with donepezil or placebo over a 12-week period
ing may be particularly relevant for clinicians deciding
suggest that the amount of cognitive change we report
whether to keep a patient on an antipsychotic treatment;
here is consistent with what may be expected from prac-
it suggests that patients who do not demonstrate early
tice effects and placebo effects (unpublished 2004 study of
cognitive benefit with a particular medication are unlikely
R. Keefe et al.). This series of results raises the question of
to show benefit with continued treatment. After 12 weeks
whether even low doses of haloperidol have a deleterious
of treatment, all correlations between cognitive improve-
impact on cognition and whether the cognitive benefit of
ment and symptom improvement were less than 0.3,
atypical antipsychotics derives from their reduced adverse
which is considered to be a medium effect, and most were
effects rather than procognitive effects. It is noteworthy,
closer to 0.1, which is a small effect (43). Thus, it is unlikely
however, that this negative effect may not occur with the
that the cognitive benefit of these antipsychotic treat-
conventional antipsychotic perphenazine, whose cogni-
ments was caused by symptom improvement. The corre-
tive effects were similar to those of atypical antipsychotics
lations with changes in symptoms were larger at 52 weeks,
in the CATIE schizophrenia trial (37).
which suggests that patients who were able to continue
Although much of our results stem from exploratory
treatment to the end of the study may have been more ho-
analyses with a large number of outcome measures not
mogeneous and were improving across all symptom do-
corrected for multiple comparisons, the pattern of results
mains or that the clinical impact on cognition may require
raises the possibility that quetiapine may have particular
benefit on tests of verbal fluency and coding, in both the
An important consequence of cognitive deficits in psy-
processing speed domain (38) and vigilance. These data
chotic disorders is functional impairment (11). However,
support previous findings (16, 19, 22) as well as conclu-
evidence that cognitive improvement with antipsychotic
sions from a meta-analysis suggesting that quetiapine has
treatment leads to functional change is limited (44). In this
a particularly beneficial impact on verbal fluency and vig-
study, patients with early psychosis who demonstrated
ilance (24). Perhaps quetiapine’s lack of appreciable affin-
cognitive improvement at 52 weeks also demonstrated
ity for muscarinic cholinergic receptors (39), which mini-
functional benefit in social and occupational domains,
mizes anticholinergic effects, and its fast dissociation
which suggests a functional relevance for cognitive im-
from striatal dopamine D2 receptors (40), which mini-
provement. One caveat to this promising conclusion is
mizes potential adverse effects on frontostriatal systems
that given the high dropout rate in this study, these data
(including reduced thalamocortical drive), allow for more
apply only to the patients who were able to stay in treat-
ment and complete comprehensive assessments for 52
COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
weeks, a group that comprised only 20% of the original
ment between University of North Carolina and the following: Wyeth,
sample. In addition, cognitive changes were not predictive
Allergan, AstraZeneca, Corcept Pharmaceuticals, Epix Pharmaceuti-cals, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Pfizer, SAS Insti-
of functional change when the analysis controlled for
tute, Schwartz, Solvey, and Somerset Pharmaceuticals. He or his wife
symptom change. Therefore, the functional benefits dem-
holds shares of stock from Amgen, Bristol-Myers Squibb, Eli Lilly,
onstrated in this study may be associated with cognitive
Genentech, Proctor & Gamble, and Sepracor. Dr. Perkins has receivedresearch funding from AstraZeneca, Bristol-Myers Squibb, Otsuka, Eli
and symptom improvement in patients who remain in
Lilly, Janssen, and Pfizer and consulting and educational fees from
treatment for substantial periods of time.
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline,Forest Labs, Pfizer, and Shire. Dr. McEvoy has received research fund-
The correlations between cognitive change and change
ing or speaking fees from AstraZeneca, Eli Lilly, and Janssen. Dr. Lie-
in side effect measures, such as tardive dyskinesia and ex-
berman has received research funding from Acadia, Bristol-Myers
trapyramidal symptoms, including akathisia, were small
Squibb, GlaxoSmithKline, Janssen, Merck, Organon, and Pfizer andholds a patent related to work with Repligen. He has also served
and not statistically significant. Furthermore, patients
without remuneration as a consultant or on advisory boards for As-
who required anticholinergic medications or reported
traZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, and Pfizer.
sleepiness did not differ from other patients in cognitive
The Comparison of Atypicals in First Episode of Psychosis research
program was coordinated by the University of North Carolina. Fund-
composite scores. These data suggest that with atypical
ing for this program was provided by AstraZeneca Pharmaceuticals
antipsychotics, side effects are not an important determi-
LP (5077IL/0114). The authors acknowledge the assistance of Anusha
nant of cognitive functioning in relatively vulnerable
Bolonna, Ph.D., of PAREXEL MMS, who provided medical writing as-sistance on the first draft of the manuscript on behalf of AstraZeneca.
early-psychosis patients with the doses used in this study.
This study is registered at www.clinicaltrials.gov under the title
One methodological issue that the data from this study
“CAFE: Comparison of Atypicals in First Episode of Psychosis” (gov-Identifier: NCT00034892, Study ID Numbers: 5077IL/0114). All crite-
address is the relative sensitivities of the CATIE neurocogni-
ria as stated in the Clinical Trial Registration policy have been met.
tive battery, which was designed specifically for the CATIEproject and requires about 90 minutes of testing time, andthe BACS, a 35-minute assessment designed to be sensitive
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